SI7910768A8 - Process for pripering 11-aza-4-0-cladinosyl-6-0-desosaminyl-15-ethyl- 7,13,14-trihydroxy-3,5,7,9,12,14-hexamethyl- oxacyclopentadecane-2-one and their derivatives - Google Patents

Abstract

11-aza-10-deoxo-10-dihydroerythromycin A and derivatives thereof, and process for preparation thereof.

Description

PROCEDURE FOR 11-AZA-4-0-KLADINCZIL-6-0-DES0ZAKINIL-15-ETYL · -7,15,14 — TRIHIDRCKSI- 5,5,7,9,12,14-HEKSAKETYLOXACYCLGFECTTA2EKAK-2-0NA AND ITS DERIVATIVES

Authors:

Gabriela Kobrehel Gorjana Radobe1ja Zrinka Tamburashev Slobodan Djokic

I \ AZ-v J.ZJLA lostunac for the preparation of 11-aza - ^ - O - cladinosyl-6-0-desosaminyl-15-ethyl-y, 13,14-cyhydroxy-3 »5,7, 9» 12 »14 -hexamethyloxycyclopentadecan-2-one and its derivatives

1. FIELD OF THE INVENTION

Int. Cl. CO7B 17/08

2. Technical problem

The subject of the invention is a process for the preparation of 11-aza-4-O-cladinosyl-6-O-desosaminyl-15-ethyl-7,13 * 14-trihydroxy-3 »5» 7 »9» 12,14-hexamethyloxycyclopentadecane-2- it (11-aza-10-deoxy-10-dihydroerythromycin 1) as well as its acyl or B- (4-R-benzenesulfonyl) derivatives, new erythromycin-type semi-synthetic antibiotics, with an expanded 15-membered azalactone ring ·

3. State of the art

The structure of the macrolide antibiotic, sri ⁺ '^ icin A (U »S. pa tent 2,653,899) is characterized by a 14-membered lactone ring and 10 asymmetric centers, erythronolide A, to which neutral sugar is attached in the C-3 and 0-5 positions. L-cladisos and basic character, D-desosamine. A number of esters have been prepared for the purpose of modifying the biological and / or pharmacokinetic properties of erythromycin A (Antibiotics Annual. 1955-195 ⁴ , Away with Svmposium Antibiotics / rfhashington DC /, 503-513 and 514-521,

U.S. patent 3 »417,077). KERNEYSOUR PLIVA ZAGREB

-2 • brake transformation! The C-9 carbonyl group of the aglycone ring was synthesized by serif iminc derivatives, including erythrocycin A oxic (Brit. Patent l, loo, 3o4), a very effective antibacterial agent, especially in the case of infections caused by gram-positive bacteria.

It is known that, under the influence of strong acids, ketoxiai are rearranged into carbamides, or, in cyclic systems, into lactams (BoubenWeyl Bd. Vll / 2b, 1986, 1976j. Organ. Beactions 11, 1, 1960; J. Org. Chem. 57, 2035. 1972; J. Org. Chem. 37, 3961, 1972).

It is also known that the Beckmann rearrangement pathway is known to be the preparation of in situ O-arylsulfoester ketoxin, and in particular p-toluenesulfonst, which in the aqueous medium is further further converted into the corresponding elbow (J. Am. Chem. Soc. 72, 5323, 1930 ?

J. Ac. Chem. Soc. 77, 109 *, 1933).

It is further known that by replacing water with solvents that can act as nucleophiles, the rearrangement is stopped at the tertiary stage, and thus the 0-alkyl- and O-arylamino ester, amidines and sulfamidines can be prepared (J. Chem. Soc. Soc. 1514, 1948; J. Am.

Chem. Soc. 80, 5660, 1936) and O-imidylphosphates (Chemistry and Industry 1183, 1953) and tetrazoles (J. Org. Chem. 15, 38, 1950).

It has now been found that the 11-aza-10-deoxy-10-dihydroerythromycin A knives are prepared by Beckmann decomposition of erythromycin A oxime with aromatic sulfochlorides and then reduction of the thus obtained

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-5products by catalytic hydrogenation or using complex metal hydrides. Also disclosed is a process for the preparation of the hitherto undescribed acyl- or N- (4-R-benzenesulfonyl) derivatives of 11-aza-10-deoxy-10-dihydroerythromycin A. New Extended Compounds The 15-membered azalactone ring exhibits better antibacterial in vitro activity over erythromycin A and erythromycin A oxime,

4. Description of the solution to the technical problem

Ae ll-aza-4-O-cladinosyl-6-O-desosaminyl-15-otyl-7 ₁ 15 »14-trihydroxy-5,5,9» 11 »15,15-hexamethyloxycyclopentadecan-2-one (11-aza-1C-deoxy-10-dihydroerythromycin A) of formula (1)

(D where R 4 is hydrogen, C 1 -C 4 alkanoyl-1-R 4 -C 6 H 4 -SO 4 groups g is R 1 -C 4 alkyl.

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R ₂ and K} and £ 4. "Which" © P ^{1 would} be the same ¹¹¹ different, have the meaning of hydrogen, C 1 -C 6 alkyl and noyl groups iii R ₄ and R- together have the meaning of a carbonyl group.

R ^ hydrogen iii together b R ^ has the equation of a carbonyl group, can be prepared by Beckmann rearrangement of erythromycin A oxime of formula (2)

with aromatic sulfochlorides in the presence of inorganic bases, in a mixture of acetone and water, followed by the reduction of the intermediate obtained catalytic or in the presence of complex metal hydrides, yielding 11-aza-10-deoxy-10-dihydroerythromycin A of formula (1), eu B _lt R ^ »R ^, \ i» are individually the same and have the meaning of hydrogen, which is subjected, if necessary, to the acylation reaction with carboxylic anhydrides or aromatic sulfochlorides or the process of transesterification with ethylene carbonate to give 11-aza-10-deoxy-10-dihydroerythromycin A

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of formula (1), where Rp is R ₂ ^{and are the} same with each other and have the hydrogen equation and R. and E- together have the equation of a carbonyl group, which is optionally subjected to an acylation reaction with carboxylic anhydrides.

According to the present invention, Beckmann rearrangement of erythromycin A oxime is carried out with 1-2 moles of aromatic sulfochlorides of the formula 4-RC ₆ H _in -S0 ₂ Cl »where R and the * equation of alkyl radicals (methyl), and 2-4 moles of inorganic baea (RaHCO ^) at C-5 ° C, in a mixture of acetone and water or another inert solvent.® * Completed reactions · (about * hour), the acetone is evaporated off under reduced pressure and the resulting aqueous suspension extracted with methylene chloride or some other solvent at pH 5 · 5 »6.0 and 8.0. The extracts extracted at pE 8.0 dried me over K ^ CO ^ and evaporated at reduced pressure to give the product with the following physicochemical constants: K ⁴ 7jo,

Tt 126-1J1 ° C, IS (CHClj) 17J0 and 1705 e »* ¹ , ^1J C HKE (CBC1 _} ) 16J.« Ppm (C-10).

The resulting product then reduces me ktalytically or through the use of complex metal hydrides. The catalytic reduction is carried out at room temperature in a high pressure autoclave at a hydrogen pressure of from about 500000 to about 7100000 Pa in glacial acetic acid or another inert solvent. As a catalyst! precious metals or their oxides may be used, such as apr. Sh / C iii PtOg. The final hydration salon (2 to 24 hours) was filtered, the filtrate was evaporated to a thick syrup, the residue was dissolved in water and extracted with methylene chloride, chloroform or other solvent at pB 6.0, 6.5 and

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-68.5 · The conjugated tetracts at pB 8.5 ® ⁱⁿ ^ ^e * ^Bad IgCO ^ ** were evaporated to dryness to teach ll-ata-10-deoxy-10-dihydroerythromycin A of formula (1), where R ^, R ₂ . Ej, E ₄ and R ^ are the same with each other and have the hydrogen equation ·

Reduction of the "need" of complex methane hydrides, such as _y SaBH. is translated by degrees the addition of "solid reagent at a temperature of about 4 ° C crosses about 4 Batts to a methanolic solution of the product obtained by Beckaann's digestion of erythromycin A oxime, and is saturated by the usual method of" extraction and salt of crude 11-ase-10-deoxy-lO » -Dihydroerythromycin A. The resulting precipitate is suspended in the ether, the suspension of the mixture is cooled with ice for about 2 hours, filtered and the filtrate is evaporated as croaatographically pure (dimethylformaide: methanol 5: 1) P ¹ * ⁰ duct.

It has now also been found that acylation of 11-asa-10-deoxy-1G-dihydroerythromycin A is a carbonic anhydride of the formula Εθ-Ο-R ?, where R ^ and R? having the C 1 -C 1 alkanoyl group equation, can prepare the corresponding 2 ', B-diacid derivatives of formula (1), wherein R 1 and R 2 are the same or small and have the C 1 -C 6 alkanoyl group equation, and R 4, R 4 and R ^ su guides, 2i4, H-triac derivatives of formula (1), gdje su R, R ₂ and R medjusobno same iii rasličiti i Eligible equation of C ^ C ^ alkanoyl groups, and R ₄ and R ^ su humor at , respectively 2'13, ΐ-tetraacyl derivatives of foreule (I), where fij, R ₂ , E _x and R ₂ are the same or different and have the equation C 1 -C 6 alkanoyl group and R 4 is hydrogen · Depending on use The reaction is carried out at a temperature of O-2 $ ° C in pyridine,

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....... * · · - / isolation by conventional methods (J · Kad. Chem. 15 * θ51 »1972) · By the hydrolysis of 2 ^ K-diaeyl derivatives in» ethanol and the addition of aqueous RaHCOj solutions can be prepared to corresponding C-acyl derivatives of the formula (1), gdje R has the equation of C ^ C ^ alkanoyl groups, and R _2, B ^ and B ^ au medjueobno the same and have the meanings of hydrogen by ·

The reaction of oz-11-aza-10-deoxy-10-dihydroerythromycin A with ethylene carbonate with the presence of IgCO2 in ethyl acetate, toluene or another inert solvent gives aa 11-aza-10-dioxo-10-dihydroerythromycin and cyclic 15,14-carbonate of formula (1), where eu R ^, R ₂ and Bj are the same with one another and have the meaning of hydrogen, and B ^ together have the meaning of a carbonyl group, which by acylation a and the carbonic anhydrides of the formula R ^ -OR ?, where Βθ and R? has the meaning of a C 1 -C 6 alkanoyl group, gives the corresponding acyl derivatives of formula (1), where and in R 2, Bg and B 2 are the same or different between them and have the meaning of a C 1 -C 6 alkanoyl group, and R 4 and B 2 together represent a carbonyl group.

The reaction of "H-aza-10-deoxy-o-10 = dihydroerythrosiases is 2-6 nv _A from aromatic eulfochlorides of the formula Α-Β-ΟθΒ ^ -βΟ ^ ΟΙ, where R has the meaning of a lower alkyl radical, halogen or lower alkanoylamino group. in acetone or another inert solvent, in the presence of sichals, such as HagCO3, prepared in the corresponding B- (4-R-benzenesulfonyl) derivatives of formula (1), where B ^ has the meaning 4-Β-ΟθΕ ^ -BO ^ -groups, and R has the meaning as stated above.

In the aftermath of antibacterial activity testing, some of the newly prepared apoj tested in vitro on a series of gram-positive

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-9 and gram-negative microorganisms. The results of au shown in Table 1 as minimum inhibitory concentrations (KICs) expressed in mcg / nl in comparison with erythromycin A and erythromycin A oxyBOB.

By examining acute i.v. tokaiity in white nicks by the Litchfield-Wilcozon method, ll-aza-10-deoxy-10-dihydroerythromycin A dream was found to be more toxic than starting erythromycin A okaima (Table 2). "

Table 2 ·

Erythromycin A okim 11-aza-10-deoxy-10-dihydroerythromycin A (LD ^ q) mg / kg 74 110

In order to determine the stability of new apogas in an excretory medium secreted in the separation of 1 B SCI at pE 1.2 for 50 minutes,

1, 2, 5, and β hours, and then the residual Tet test substance activity was determined as minimum inhibitory concentration (KIK) in * cg / m 1 with the help of the Staphjlocoecue aureus ATCC 655 & -P test organism. azs-10-deoxy-10-dihydroerythromycin A and its cyclic 15,14-carbonate range within the stability of erythromycin A oxime, medullin to erythromycin A newly prepared compounds and significantly more stable at pE 1.2, therefore, conditions that mimic the situation a gastrointestinal tract (Table 5).

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Tables 5,

Time and * lag of acid action (h) E EC Λ c 10 ⁺ 0 0.5 0.1 0.5 1.0 1/2 7.5 0.1 0.5 3 _t 0 1 10 0.1 0.5 1.0 2 10 0.5 1.0 2.5 3 10 0.5 1.0 2.5 6 20 C.5 1.0 2.5

E · erythroaicin 1 EO erythroaicin A oxin ⁺ Arabian broilers denote the number of priyer.

SOUB PLIVA ZAGREB .L; / '- -11 Finding it illustrates or illustrates the examples which limit the lirinv of this invention.

Example 1.

Beckmann rearrangement of erythromycin A oxime

Solutions of p-toluenesulfochloride (6.16 g, 0.032 mol) in acetone (70 ml) and BaSCO3 (5.4 g, 0.064 mol) in water (245 ml) were added dropwise by stirring at a temperature of O to 5 ° 0 kr or 2 aat. erythromycin A oxime (12 g, 0.016 mol) in acetone (200 ml). The reaction of the heart myofia was continued for two hours at the same temperature, the acetone was evaporated by evaporation under reduced pressure, methylene chloride (50 ml) (pE 7.9) was added to the aqueous solution, followed by acidification, and then acidified with 1 K ECI pE to 5 · 5 · The layers were separated and the aqueous extracted twice more with 50 ml of methylene chloride. Extraction with methylene chloride was repeated to pE 6.0 (3 x 50 ml) and pE 6.0 (5 x 100 ml) combined organic extracts dried over EgCO ^ ⁱⁿ P ^are reduced pressure »At pE 8.0, 6.4 g of the product having a physicol- chemical constants _x ~ _

Mp 128-131 ° C / <^ 4 ° - ->. 63 (1%. CE ₂ C1 ₂ )

IR (CBCl): 1725 (CO, lactone) and 1705 cm &lt; ¹ &gt; (-OCB-) ¹⁵ C FMR (CDCl3): 163.9 ppm (-OCK-)

M * 730

Example 2.

11-Aza-10-deoxy-10-dihydroerythromycin A (Method 1)

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-126.0 g (ΟΟ.ΟΟ6 · ο1) of the crude product from the 1st era is dissolved in ice-white whiteness (6C tl), added to PtO ^ (0.25 g) * and hydrated to the aunt by mixing 2 « At a pressure of 7100000 Pa, the Catalyst is filtered off, the filtrate is evaporated under reduced pressure to a thick syrup, dissolved in water (160 tl) and extracted with methylene chloride: at pB 6.0 and 6.5 (3 2> 0 al) and pE 6.3 (3 x 100 alk The combined ecetrack at pB 8.3 «learns from ^ 00 ^ ^and evaporates at reduced pressure to give 4.8 g of cross-graphotically pure (dimethylformamide: methanol 3: 1) l-asa-10-deoxy-10-dihydroerythromycin A.

T.t. 113-116 ° C · -53.91 (1%, C ^ Cip

IR (CHCl3): 1725 (0.0 lactone) and 1640 ob * ¹ (-KB-) ¹⁵ CNMS (CDC1 ₅ ): 56.8 ppe (C-10)

K * 73 *

Example 3 · 11-Asa-10-deoxy-10-dihydroerythrocycin A (Method 2)

2.0 g (0.0027 µol) of the crude product from the first product was dissolved in glacial acetic acid (20 ml), 1.0 g of Rh / C was added 5%, and with a shining bath, hydrated for 8 hours at a pressure of 6500000 Pa * The catalyst was filtered off , s isolates the product according to the method described in the example

2. 1.3 g of the product with the physicochemical conetantame identical to the product of Example 2 were obtained.

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-15Example 4, 11-Aza-10-deoxyBo-10-dihydroerythromycin A (Method 3)

Γ A solution of 12 g (0.016 mol) of the crude product of Example 1 in absolute methanol (500 b1) was added gradually over 4 hours with Bishing at a temperature of about 4 ° C solid HaBH 2 (12 g, 0.516 salt). After 24 hours at room temperature, the reaction mixture was introduced (Χ> 2 to stop settling, the precipitate formed was filtered off and the filtrate evaporated under reduced pressure. The resulting precipitate was dissolved in chloroform (500 b1), the chloroform solution was washed with 10 % solution of HaHCO3 and water (2 z 150 b1), dried over 1 H 2 CO 4, filtered and evaporated under reduced pressure, the bean product was dissolved in chloroform (100 ml), but water (500 al) was dissolved (pE 11.5) the acid resonance with acid from 2 E BC1 to pB 2.5 and stirred for 15 minutes at room temperature, the pE of the reaction solution was adjusted with 20 $ b-KaOE to 6.0, the layers were separated and the aqueous layer was extracted twice more 6 Extraction with chloroform was repeated on pE 6.

(5 z 50 al) and pB 6.5 (5 z 50 b1), the combined chlorophorean extracts were dried over E ^ CO ^ and evaporated under reduced pressure. The precipitate obtained at pB 8.5 was suspended in ether, stirred for 2 hours under ice-cooling, filtered and the filtrate evaporated as chromatographically pure (dimethylforamide: methanol 5: 1) 11-aza-10-deoxy-10-dihydroerythromycin A, identical physical-chemical constants as the substance obtained in prim ru 2.

Example 5 ·

2 * .B-Diacetyl-11-aza-10-deoxy-10-dihydroerythromycin A

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-14—

To the solution of 11-aza-10-deoxy-10-dihydroerythromycin A (4 g, O.OO5 * ol) n pyridine (60 al) was added the hydrochloric acid anhydride (50 al) and allowed the reaction solution to stand for 30 ains at ambient temperature . The acylation reaction was quenched with ice, pB adjusted with 20% RaOE to 9.0 and extracted with chlorophyll (3 x 75 al).

The combined chloroform extracts were washed with water (2 x 75 al), dried over Na 2 CO 2 and evaporated at the desired pressure. The resultant product was followed by i2 ethers with petroleum ether. Utilization 5 · * £ (76.4%) »

T.t. 13> 158 ° C ρΚ ^ 6.7 (dimethylformaaid-water, 66% v / v)

IR (CBCl) and 1725 (C-0, lactone), 1610 (-00-K <) and 1255 ca ¹ (acetyl)

Priajar 6.

2 ', K-Dipropionyl-11-aza-10-deoxy-10-dihydroerythromycin A

From 2.0 g (0.0027 mol) of 11-aza-10-deoxy-10-dihydroerythroaicin A and 25 al (0.19 * aol) propionic acid anhydride by reaction in pyridine (40 ai> zylorous), 5 · 1.35 g (57.6%) of chromatographically pure (chloroform: methanol 7: 3) 2 *, Bdipropionyl-11-aza-10-deoxy-10-dihydroerythroBicin A ·

T.t. 185-186 ° C pEb 6.7 (dimethylformaaid-water, 66% v / v)

IR (CHCl3): 1725 (C »O, lactone and ester), 1615 (-ΟΟ-Ηζ ·) and 1175 ci ^ (propionyl)

Example 7 ·

2 * .h ^ .K-Triacetyl-11-aza-10-deoxy-10-dihydroerythromycin A

60UE SWIMS ZAGBEE. .-15U solution of 11-aza-10-deoxy-10-dihydroerythromycin A (1.0 g,

0.001> 6 Dol) in pyridine (PO ml) was added acetic anhydride (20 sl, 0.212 mol) and the reaction was aged at room temperature for 76 hours. The reaction is quenched by the addition of ice, the pB of the reaction mixture is raised from 20% RaOB to 9.0, and then the product is isolated by extraction ~ 1 ^λ τ * ο £ ογβοβ (5 x 50 Bi). The combined chlorophoretic extracts were washed with saturated solution of KaHCO3 (5 z y> ml) and water (2 x 50 ml), dried over K ^ OO ^ and evaporated under reduced pressure. The crude product is precipitated from chloroform and petroleum etherB. Use Wear 0.72 g (61 ·%) of chromatographically pure (chloroform: methanol: * formamide 100: 20: 2) triethyl ethyl derivative.

T.t. 148-156 ° C / e £ ^ -31.5 (diBethylformamide-water, 66% v / v)

IB (CHCl3): 1735 (C »C, lactone and ester), 1625 (-CO-Βζ) and 1235 ca ' ¹ (acetyl)

Example 8.

2 * .4 \ 13.B-Tetraacetyl-11-aza-10-deoxy-10-dihydroerythromycin A To a solution of 11-aza-10-deoxy-10-dihydroerythromycin A (1.5 8 »0.002 aol) was added acetic anhydride (15 al, 0.159 mol) and then the reaction solution was aged to stand at room temperature for 10 days. The reaction was quenched with ice, and the product was isolated by analogy as the triaeethyl derivative in Example 7. By several consecutive precipitation of the crude product from chloroform with petroleum ether, 1.42 g (77%) of 2 *, 4 ', 13 ₁ R-tetraacetyl-11-aza- 10-deoxy-10-dihydroerythroaicin A ·

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Mp 11O-115 ° C / <f / p ° - -55.45 (1%, CH ₂ C1 ₂ )

IB (CHC1 ₅ ): 1755 (C 0, lactone and ester), 1625 (-CO-Νζ) and 1240 cm ¹ (acetyl)

K ⁴ 902

Example 9 ·

K-Propionyl-11-aza-10-deoxy-10-dilihydroerythromycin A

To a solution of 2 * »K-dipropionyl-H-aza-10-dioxo-10-dihydroerythromycin A (2.15 g, 0.00254 mol) in methanol (45 ml) was added a 54-solution of FaHCO3 (45 ml) and aged to stand. 7 days at room temperature · Methanol is evaporated under reduced pressure, the pH of the aqueous suspension with 204 BaOB is adjusted to 9.0 * then extracted with chloroform (5 x 5θ »1) · The combined chlorophyll plow extracts are foamed with water (2 z 50 ml), dried over I ^ CO ^ and evaporated under reduced pressure. Yield 1.84 g (92.64).

T.t. 122-129 ° C pk ^ 8. L (dimethylforaaaid water, 664 v / v)

IR (CHCl3): 1720 cm &lt; ¹ &gt; (C-0, lactone) and 1620 (-OO-RC).

Example 10.

11-Aza-10-deoxy-10-dihydroerythroaicin A cyclic 15.14-carbonate

To a solution of 11-aza-10-deoxy-10-dihydroerythromycin A (1.0 g, 0.0015 * mol) in ethyl acetate (10 ml) was added 0.2 g (0.0014 mol) of CO 2 and 0.5 g (0.00568 mol) of ethylene carbonate and then two hours of cube floor

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...... ------- '- -17refrigerant. The reaction mixture was cooled to dryness, filtered and evaporated under reduced pressure to a thick oily residue, which, with the addition of water (about 25 ml), precipitated 11-ama-10-deoxy-10-dihydroerythromycin A cyclic 13,14-carbonate (0.85 8 «82.1%).

T.t. 129-155 * 0

IR (CHCl3): 1790 (C »0, carbonate) and 1725 cm @ ^-1 (0 * 0, lactone)

K *? 60

Example 11,

2 *. »\ K-Tria & ethyl-11-ana-10-deoxy-10-dihydroerythroBicin A Cyclides 13.14-Carbonate

To a solution of 11-ama-10-deoxy-10-dihydroerythromycin A cyclic

13.14-carbonate (0.5 St 0.00065 mol) in pyridine (2.5 ml) was added acetic anhydride (2.5 ml, 0.00265 mol) and allowed to stand at room temperature for 28 hours. The reaction was quenched with ice and the product was extracted with chloroform extraction (3 x 15 ml). The combined chlorophorean extracts were washed with water (2 x 10 ml), dried over CH2 Cl2 and evaporated under reduced pressure. Yield 0.56 g ·

T.t. 1O9-117 ° C

IR (CHCl3): 1800 (C-0, carbonate), 1750 (C-0, lactone and ester),

1625 (-CO-NC) and 1240 cm ^-1 (acetyl)

KMS (CDC1 ₅ ) j 2.06 (32), 2.1 ($ H), 2.12 (3B), 2.3 (62) and 3.3 (52) ppm

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...... '----- -18Example 12,

E- (4-ethylbenzenesulfonyl) -yl- "aza-10-deoxy-10-dihydroerythroaicin A

To a solution of 11-aza-10-dioxo-10-dihydroerythroaicin A (4.0 g, 0.0054 aol) in acetone (120 al) was added 15.8 g (0.110 aol) of N-CO 2 -hydrohydrate and zeta · P-toluenesulfochloride solution (6.24 g, 0.052gol) in acetone (120 al) was added dropwise and boiled under reflux for 12 hours. The reaction suspension was triturated and the filtrate was evaporated at the desired pressure. The resulting precipitate was dissolved in aethylene chloride (100 al), 40 al of water (pE 7.0) was added to the solution, pE was adjusted to HCl 6.0, the layers were separated with water and extracted three more times with aethylene chloride (40 al), the drying mixture was combined. of organic extracts over KpCO3 of evaporation of the solvent, 5 &apos; E of crude product is obtained which is purified by chromatography :: on a silica gel column.

Mp 15O-155 ° C / 0 ^ 20. _ _{9> 04} CBgClg)

ΙΒ (0Β01 ^) ί 1750 (GO, lactone), 1600, 755 and 6> 5 (p-phenyl) and 15 * 0 ca * ¹ (-SOg-)

M ⁺ 888

SOUR PLIVA ZAGREB

-WKAJBOUI RAČI? FOR THE USE OF PSOCALASK IN THE PRODUCTION OF 11-AZA-4-0-ELADIBOZIL-e-O-DBSOZAMIC IL-15-ETYL-7. 13.14-TRIHYBOXY-3,5.7.9,, l * -SEXAKETYLOXACl £ LOPENTADEKAB-2-ON AND BJBGOVIB DERIVATIVES

According to this invention II ~ "s" ~ "~ ri- * ladinosil-6-0-deBO" &lt; -1 &gt; inyl-1,5-ethyl-7 * 13 »14-trihydroxy-3,5,7,9,12, lA -hexamethyloxycyclopentadecan-2-one (11-aza-10-deoxy-10-dihydroerythromycin A} can be prepared in the simplest and most convenient way

A / Beekmann rearrangement of erythromycin A oxime with p-toluenesulfachloride to the presence of RaBOO ^ in acetone and water at O-5 ° C and isolation to produce a gradient of pB »ethylene chloride extraction with

B / Catalytic »hydration of an isolated product with platinum (IV) oxide in ice-vinegar at room temperature and pressure >> 70 atmospheres for 2-20 hours, depending on the pressure at which the reduction is carried out.

Bcbiveui 11-aza-10-deoxy-10-dihydroerythromyain A is, if necessary, reacted with ethylene carbonate in the presence of K ^ CO ^ to translate n 11-aza -1O-deoxy-10-dihydroerythromycin A-cyclic 13,14-carbonate.

By acylating U-aza-10-deoxy-10-dihydroerythromycin A or its cyclic 13,14-carbonate with carboxylic anhydrides such as e.g. acetic anhydride or propionic anhydride, in pyridine at a temperature of O-25 ° C, the corresponding 2 *, K-diacyl-,

2 ', 4, H-triacyl and 2', 4,13, N-tetraacyl derivatives, and hydrolymate 2 *, N-diacyl-11-aza-10-deoxy-10-dihydroerythromycin. And in the metaSOUR PLIVA ZAGREB

-20nol with the addition of 5% aqueous RaHCC solution _x appropriate R-acyl-11-aza-10-deoxy-10-dihydroerythromycin A ·

Reaction of 11-aea-10-deoxy-10-dihydroerythromycin A with an aroma of such eulfochlorides of the formula A-R-C ^ H ^ -SO ^ Cl, in which S has the equation of a lower alkyl radical, halogen or lower alkanoylamino group, such as alkali, e.g. 1a-CO 2, in acetone or another suitable solvent prepared in the corresponding H- (4-R-benzene-sulfonyl) derivatives, such as e.g. B- (4-Methyl-, K- (4-iodo-iii-β- (4-acetyl • minoenzenesulfonyl) -yl-α * - 10-deoxy-10-dihydroerythromycin A ·

SOUR PLIVA-ZAGREB Legal and Patent Affairs ManagementUac: »(Z.Bedekovič, B.Sc.)

SOUR PLIVA ZAGREB

Claims (2)

A process for the preparation of 11-az8-4-0-kledinosyl-6-0-desosaminyl-1-Sethyl-7,13,14-trihydroxy-3,5 "9" H "15" 15-hexamethyloxy cyclopentadecan-2-one ( 11-aza-10-deoxy-10-dihydroerythromycin A) of formula (1), (D where R 4 is hydrogen, C 1 -C 4 alkanoyl- or 4-R ₄ H ₄ -SO ₂ -groups, where C 1 -C 6 alkyl, R ^, Rj and R ^, who may be her. the same or different, hydrogen, θ1θ3 alkanoyl groups iii and Rj together have the meaning of a carbonyl group, R 1 is hydrogen iii together with R 1 is a carbonyl group, wherein e 1 / erythromycin 1 is an oxime of formula (2), SOUR PLIVA ZAGREB (3) .. «r · undergoes a Beckmann reaction by the reaction of a 1-2 salts of p-toluenesulfachloride and 2-4 moles of NaHCO3 at a temperature of from 0 to '5 ° C, for 4 hours, in a mixture of acetone and water, to give the product of the gross formula M ⁺ 750, m.p. 128-151 ° C, - -54.63 (1%, CH ₂ C1 _2), IR (KBr) 1750 and 1705 cm ^{"1, 15} C NMR (CDClj) 165.9 ppm (C-10) podvrgne / ^ / Catalytic hydrogenation e Rh / C 5% in glacial acetic acid, at room temperature, for 6 hours, at a pressure of 65o0000 Pa, or B ₂ / catalytic hydrogenation with PtO ₂ in glacial acetic acid at room temperature for 2 to 24 hours and hydrogen pressure 500000 to 7100000 Pa, depending on the substrate: catalyst ratio (1:24 to 1: 2) in glacial acetic acid or other inert otaoal. SOUR PLIVA ZAGREB -23B ^ Z reducing e BaBE ^ in methanol at 4 ° C for 24 hours to give 11-aza-10-deoxy-10-dihydroerythromycin A of formula (1), where R <p is R ₂ , R 1. R ^ and R ^ are read to one another and have the meaning of hydrogen, which, if necessary, subject them C ^ / acylation reaction with acetic or propionic acid kettle acid pyridine reaction at an ambient temperature for 30 minutes from zero to one day to give 2 ', Β-diacyl derivatives of formula (1), wherein R 1 and R 2 and ** are the meanings of an acetyl or propionyl group, and R 1, R 1 and R 2 are in each other and have the meanings of hydrogen, optionally subjected to hydrolysis in methanol in the presence of a 5fc aqueous NaHCO3 solution for 7 days to give the B-acyl derivatives of formula (1), wherein R ₁ has the meaning as indicated above and R ₂ , R 4, R 4 and R 4 and in the meantime read and have the meaning of hydrogen, or 2 *, 4 ~, N-triacyl derivatives of formula (1), wherein R 1, R ₂ and R ₂ have the meaning of acetyl and R ₂ and R 4 are the same and have a hydrogen irradiation, or 2 *, 4 ~, 13, N-tetraacyl derivatives of formula (1), where 1 _χ , Rg, R ^ and R have the meaning of acetyl and R ^ is hydrogen, or ae is subject to .SOUR FLIVA ZAGREB Cg / reaction a 1-4 by the impact of ethylene carbonate in ethyl acetate, at the reflux temperature of the solvent, for 2 hours, yielding 15.14-cyclic carbonate of formula (1), is bu R ^, R ^ and having the meaning of a carbonyl group, which ae optionally undergoes acylation reaction with acetic anhydride in pyridine at room temperature for 2 days to give the 2 ', 4 ~, N-triacyl derivative of formula (1), where au R ^, Rg and Rj are the same and have meaning acetyl, and R ^ and Rr together are carbonyl groups, iii ae subjected 4-R-CgHq- »SO2Cl, where R is the meaning of the methyl group, in acetone, in the presence of Na2CO4, at the reflux temperature of the solvent for 12 hours to give N- (4-R-benzenesulfonyl) derivatives of formula (1), where R ^ has the meaning as indicated above, and R ₂ , Rj, R ^ and au are the same and have the meaning of hydrogen » 2, The process of claim 1, wherein the inert solvent is catalytic hydrogenation with PtC4 alkanol.